The hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide. Following acute HCV infection, only 15-45% of individuals resolve the virus spontaneously. Clearance of HCV infection requires the generation of potent antiviral T cell effectors. Virally encoded proteins are known to induce a dysregulated activation state In peripheral blood monocytes, and cytokines from aberrantly activated monocytes can adversely affect T cell priming by dendritic cells. In preliminary studies, we have shown that polymorphisms of the Killer Immunoglobulin Receptor (KIR) family of NK cell receptors and their human leukocyte antigen (HLA) class I ligands are major host determinants of spontaneous HCV clearance; that acute HCV infection triggers NK cell activation pathways involving the natural cytotoxicity receptor NKG2D; and that stress-inducible cell-surface ligands for NKG2D are expressed on HCV-activated peripheral blood monocytes. We hypothesize that NK cells may promote effective T cell priming by clearing aberrantly-activated monocytes and virally infected cells, or by contributing to the elaboration of potent antiviral cytokines. Moreover, we propose that effector and cytokine responses of NK cells may be triggered, in part, by NKG2D and modulated by inhibitory and activating KIR, and that NK cells with a memory phenotype may contribute directly to adaptive antiviral responses. In this Project, we will perform multivariate analysis of NK cell receptor profiles, NK cell effector and memory responses, monocyte activation states, and cytokine networks in the context of treatment-induced HCV eradication. These studies will be performed using specimens of peripheral blood and liver biopsies from patients in a retrospective case-control study and a prospective study of response to standard-of-care treatment of HCV infection. We wish to determine: (1) whether polymorphic receptors controlling NK cell activation predict divergent antiviral treatment responses in chronic HCV and whether the acquisition of memory NK cells correlates with viral eradication; and (2) whether specific NK cell and monocyte/macrophage activation and cytokine profiles contribute to successful treatment-induced clearance of HCV infection. These results will be analyzed in concert with those obtained on adaptive immunity in Project 2.